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CNS Neurosci Ther. 2013 Oct;19(10):820-33. doi: 10.1111/cns.12151. Epub 2013 Jul 27.

Hypoxia-triggered m-calpain activation evokes endoplasmic reticulum stress and neuropathogenesis in a transgenic mouse model of Alzheimer's disease.

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  • 1Department of Pathophysiology, Key Laboratory of Medical Cell Biology of Ministry of Education of China, China Medical University, Shenyang, China; Medical Research Laboratory, Jilin Medical College, Jilin, China.



Previous studies have demonstrated that endoplasmic reticulum (ER) stress is activated in Alzheimer's disease (AD) brains. ER stress-triggered unfolded protein response (UPR) leads to tau phosphorylation and neuronal death.


In this study, we tested the hypothesis that hypoxia-induced m-calpain activation is involved in ER stress-mediated AD pathogenesis.


We employed a hypoxic exposure in APP/PS1 transgenic mice and SH-SY5Y cells overexpressing human Swedish mutation APP (APPswe).


We observed that hypoxia impaired spatial learning and memory in the APP/PS1 mouse. In the transgenic mouse brain, hypoxia increased the UPR, upregulated apoptotic signaling, enhanced the activation of calpain and glycogen synthase kinase-3β (GSK3β), and increased tau hyperphosphorylation and β-amyloid deposition. In APPswe cells, m-calpain silencing reduced hypoxia-induced cellular dysfunction and resulted in suppression of GSK3β activation, ER stress and tau hyperphosphorylation reduction as well as caspase pathway suppression.


These findings demonstrate that hypoxia-induced abnormal calpain activation may increase ER stress-induced apoptosis in AD pathogenesis. In contrast, a reduction in the expression of the m-calpain isoform reduces ER stress-linked apoptosis that is triggered by hypoxia. These findings suggest that hypoxia-triggered m-calpain activation is involved in ER stress-mediated AD pathogenesis. m-calpain is a potential target for AD therapeutics.


APP/PS1 transgenic mouse; Alzheimer's disease; Calpain; Endoplasmic reticulum stress; Glycogen synthase kinase 3; Hypoxia; RNA interference

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